version 3 - sfda

Version 3.0

Date of issue 18 August 2016

Date of implementation 1 July 2018

2

Data Requirements for Veterinary

Medicinal Products

Pharmaceutical and Immunological

Version 3.0

Saudi Food & Drug Authority

Drug Sector

For Inquiries [email protected]

For Comments [email protected]

Please visit SFDA’s website at

https://www.sfda.gov.sa/en/regulations?tags=2

for the latest update

mailto:[email protected]



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Saudi Food and Drug Authority

Vision and Mission

Vision

To be a leading international science-based regulator to protect and promote

public health

Mission

Protecting the community through regulations and effective controls to

ensure the safety of food, drugs, medical devices, cosmetics, pesticides and

feed

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Document Control

Version Author Date Comments

1.0 Drug Sector February 2016 1st draft

1.1 Drug Sector April 2016 Internal review

1.2 Drug Sector June 2016 2nd internal review

1.3 Drug Sector August 2016 Draft for public review

2.0 Drug Sector 1 July 2018 Final Version

3.0 Drug Sector 02 June 2021 Update

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What is New in version no. 3.0? The following table shows the update to the previous version:

Section Description of change

II. Part 1 Summary of

the dossier for

Pharmaceutical and

Immunological Veterinary

Medicinal Products

Update:

1a Administrative Information

- 1a7 Additional Data

o Information relating to the administration

of the veterinary medicinal product not

covered by the previous sections may be

included in this section.

III. Data Requirements

for Veterinary

Pharmaceutical Products

Add:

2b Description of the Manufacturing Method

- 2b1: Manufacturer and Batch Formula

- 2b2 Description of the Manufacturing

Process and Process Controls

- 2b3 Facility, Equipment, Controls of

Critical Steps and Intermediates

- 2b4 Process Validation and/or Evaluation

Add:

2e Tests on the Finished Product

- 2e1 Specifications of the Finished Product

Add:

3b Residue tests

- 3b1 Introduction

Update:

2c1 Active Substance(s)

- 2c1.1 Detailed Requirements of the Active

Substance (API)

Update:

2c3 Container Closure

- 2C3.1 Active Substance

- 2C3.2 Finished Product

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Update:


- 2e1 Specifications of the Finished Product)

- 2e2 General Characteristics of the Finished

Product

- 2e3 Identification and Assay of Active

Substance(s)

- 2e4 Identification and Assay of Excipient

Components

Update:

2f Stability tests

- 2f1 Active Substance

- 2f2 Finished Product

IV. Data Requirements

for Veterinary

Immunological Products

Update:

2g Stability

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Contents

I. Introduction ............................................................................................................... 9

1. For Veterinary Generic Products ......................................................................... 9

2. Similar Biological Veterinary Medicinal Products ........................................... 10

II. Part 1 (Summary of the dossier) for Pharmaceutical and Immunological

Veterinary Medicinal Products ...................................................................................... 12

1a Administrative Information .................................................................................. 13

1b SPC and Product Literature ................................................................................ 16

1c Critical Summaries (CS) ....................................................................................... 17

III. Data Requirements for Veterinary Pharmaceutical Products ........................ 18

Part 2 Quality Documentation ................................................................................. 20

2a Qualitative and Quantitative Particulars ......................................................... 20

2b Description of the Manufacturing Method ...................................................... 22

2c Control of Starting Materials ............................................................................ 23

2d Control Tests at Intermediate Process Stages ................................................. 30

2e Tests on the Finished Product ............................................................................ 30

2f Stability Tests....................................................................................................... 34

2g Other Related Documents .................................................................................. 35

Part 3 Safety and Residues Tests ............................................................................. 36

3a Safety Tests .......................................................................................................... 36

3b Residue Tests....................................................................................................... 46

Part 4 Preclinical and clinical trials......................................................................... 50

4a Pre-clinical Requirements .................................................................................. 50

4b Clinical Requirements ........................................................................................ 53

IV. Data Requirements for Veterinary Immunological Products ......................... 58

Part 2 Quality Documentations ................................................................................ 61

2a Qualitative and Quantitative Particulars ......................................................... 61

2b Description of the Manufacture Method .......................................................... 63

2c Production and Control of the Starting Materials .......................................... 63

2d Control Tests during the Manufacturing Process ........................................... 66

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2e Control Tests on the Finished Product ............................................................. 67

2f Batch-to-Batch Consistency ............................................................................... 68

2g Stability ................................................................................................................ 68

2h Other Information .............................................................................................. 69

Part 3 Safety Documentation ................................................................................... 70

3a General Requirements ....................................................................................... 70

3b Laboratory Tests ................................................................................................ 70

3c Field Studies ........................................................................................................ 74

3d ERA (Environmental Risk Assessment) ........................................................... 74

3e Assessment of Products Containing or Consisting of GMO (Genetically

Modified Organisms) ............................................................................................... 75

Part 4 Efficacy documentation ................................................................................ 76

4a General Principles .............................................................................................. 76

4b Performance of Trials ........................................................................................ 76

4c General Requirements ........................................................................................ 76

4d Laboratory Trials ............................................................................................... 78

4e Field Trials........................................................................................................... 78

V. References ................................................................................................................. 79

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I. Introduction

This guidance published to assist applicant in the preparation of Veterinary medicinal

products submissions for presentation to Saudi food and drug authority (SFDA).

The data requirements for veterinary medicinal product for each application will differ,

based on the type of product pharmaceutical or immunological. However, presentation and

content of part 1 (summary of the dossier) is similar for both types and will differ in Parts

2, 3 and 4:

For pharmaceutical product; Parts 2, 3 and 4 of the dossier consist of quality, safety

and residues tests and preclinical and clinical respectively.

For immunological product; Parts 2, 3 and 4 of the dossier consist of quality, safety

and efficacy respectively.

About preparing the dossier for generic and similar biological veterinary medicinal

products, it is acknowledged that certain parts or sections would generally not be

applicable, as explained in the following sections:

1. For Veterinary Generic Products

The dossier shall contain the data referred to in Parts 1 and 2 with an environmental risk

assessment and data demonstrating that the product has the same qualitative and

quantitative composition in active substances and the same pharmaceutical form as the

reference medicinal product and data showing bioequivalence with the reference medicinal

product.

The detailed and critical summaries on safety and efficacy shall particularly focus on the

following elements:

- the grounds for claiming essential similarity,

- a summary of impurities present in batches of the active substance(s) as well as

those of the finished medicinal product (and where relevant decomposition

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products arising during storage) as proposed for use in the product to be marketed

together with an evaluation of these impurities,

- an evaluation of the bioequivalence studies or justification as to why studies were

not performed concerning to established guidance,

- if applicable, additional data in order to demonstrate the equivalence of safety and

efficacy properties of different salts, esters or derivatives of an authorised active

substance shall be provided by the applicant; those data shall include evidence that

there is no change in the pharmacokinetic or pharmacodynamics properties of the

therapeutic moiety and/or in toxicity, which could influence the safety/efficacy

profile.

For products intended to be administered by intramuscular, subcutaneous or transdermal

routes, the following additional data shall be provided:

- evidence to demonstrate equivalent or differing depletion of residues from the

administration site, which may be substantiated by appropriate residue depletion

studies,

- evidence to demonstrate target animal tolerance at the administration site, which

may be substantiated by appropriate target animal tolerance studies.

2. Similar Biological Veterinary Medicinal Products

Where a biological veterinary medicinal product which is similar to a reference biological

veterinary medicinal product does not meet the conditions in the definition of the generic

medicinal product, information to be supplied shall not be limited to Parts 1 and 2,

supplemented with bioequivalence and bioavailability data. In such cases, additional data

shall be provided, in particular on the safety and efficacy of the product:

- The type and amount of additional data (i.e. toxicological and other safety studies

and appropriate clinical studies) shall be determined on a case-by-case basis in

accordance with relevant scientific guidelines.

- Due to the diversity of biological veterinary medicinal products, SFDA shall

determine the necessary studies foreseen in Parts 3 and 4, taking into account the

specific characteristic of each individual biological veterinary medicinal product.

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If the reference biological veterinary medicinal product has more than one indication, the

efficacy and safety of the biological veterinary medicinal product claimed to be similar

shall be justified or, if necessary, demonstrated separately for each of the claimed

indications.

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II. Part 1 (Summary of the dossier) for Pharmaceutical and

Immunological Veterinary Medicinal Products

Section Requirements


1a1 Cover Letter

1a2 Application Form

1a3 Pharmacovigilance

1a31 Pharmacovigilance System

1a32 Risk Management Plan

1a4 Certificates and Documents

1a41 GMP Certificate

1a42 CPP

1a43 Certificate of Analysis – Drug Substances & Finished Product

1a44 Certificate of Analysis - Excipients

1a45 Certificate of Suitability

1a46 Patent Information

1a47 Letter of Access or Acknowledgment to DMF

1a5 Pricing

1a51 Price List

1a52 Other Documents Related

1a6 Responses to Questions

1a7 Additional Data

1b SPC and Product Literature

1b1 Summary of Product Characteristics (SPC)

1b2 Package Leaflet (PL)

1b21 Arabic Leaflet

1b22 English Leaflet

1b3 Labeling

1b4 Artwork (Mock-ups)

1b5 Samples

1c Critical Summaries

1c1 Quality

1c2 Safety and Residues

1c3 Efficacy

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1a1 Cover Letter

The applicant shall include a cover letter for each submission. A template provided in the

SFDA Guidance for Submission.

1a2 Application Form

The completed and signed application form printed out from the Saudi Drug Registration

(SDR) system (https://sdr.sfda.gov.sa/frmLogin.aspx) should be presented in this section.

1a3 Pharmacovigilance

1a31 Pharmacovigilance System

It shall contain a detailed description of the pharmacovigilance system including the proof

that the applicant has the services of a qualified person responsible for pharmacovigilance

and the necessary means for the notification of any adverse reaction.

1a32 Risk Management Plan

A detailed description of the risk management system, which the applicant will introduce,

should provide, where appropriate.

1a4 Certificates and Documents

1a41 GMP Certificate

A valid GMP Certificate should be submitted.

1a42 Certificate of Pharmaceutical Product (CPP)

The CPP should be in accordance with WHO guidelines. However, if the CPP is not

available, a marketing authorization (or free sales certificate) from the country of origin

(COO) should be submitted. Marketing authorization (or free sales certificate) should

include the following:

1. Product trade name in the COO.

2. Number and date of marketing authorization in the COO.

3. Name of active and inactive substances with their concentrations.

https://sdr.sfda.gov.sa/frmLogin.aspx

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4. A statement that certifies the product is marketed in the COO. If not, please specify

the reasons.

5. Provide official document demonstrating that the product has registered for no less

than one year in the COO.

6. Provide the Summary of Product Characteristics (SPC).

7. Provide a copy of the Package Leaflet (PL).

1a43 Certificate of Analysis – Drug Substance and Finished Product

- Certificates of analysis for more than one batch of the drug substance should

submitted from the supplier (drug substance manufacturer).

- Certificates of analysis for more than one batch of the drug substance should be

submitted from the finished product manufacturer.

- Certificates of analysis for more than one batch of the finished product should

submitted.

1a44 Certificate of Analysis – Excipients

Certificates of analysis for more than one batch of the excipients may submitted to support

the application.

1a45 Certificate of Suitability for TSE

Data should be provided to confirm that the drug substance, starting materials and reagents

and/ or culture media used to manufacture of the veterinary medicinal products

are submitted according to Note for guidance on minimising the risk of transmitting animal

spongiform encephalopathy agents via human and veterinary medicinal products. When

available, a CEP demonstrating TSE-compliance should be submitted. A complete copy of

the CEP (including any annexes) should be provided.

1a46 Patent Information

This section should contain a declaration letter on an official company letterhead stating

the patent status of the product.

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1a47 Letter of Access or Acknowledgment to DMF (If applicable)

A letter was written by the DMF Owner or authorized Agent permitting SFDA to reference

information in the DMF on behalf of the Applicant. For more information about the

certificates that must authenticated refer to the DMF: Guidance for Submission.

1a5 Pricing

1a51 Price List

The applicant shall include the price of the product in countries listed in the SFDA

Guidance for Submission.

1a52 Other Documents Related

1a6 Responses to Questions

The response document should follow the same presentation as the initial dossier. The

applicant should include in this section a document, which lists the questions with the

corresponding narrative text response for each question. This section will not use for

supporting technical documentation, which will be included to the relevant Parts. Each

question should followed by the name of section, page number and a hyperlink where the

answer can be found in the concerned part.

1a7 Additional Data

Information relating to the administration of the veterinary medicinal product not covered

by the previous sections may be included in this section.

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1b SPC and Product Literature

1b1 Summary of Product Characteristics (SPC)

Refer to the Guidance for presenting the SPC, PL and labeling information for veterinary

products.

1b2 Package Leaflet (PL)

Refer to the Guidance for presenting the SPC, PL, and labeling information for veterinary

products.

1b21 Arabic Leaflet

1b22 English Leaflet

1b3 Labeling

Refer to the Guidance for presenting the SPC, PL, and labeling information for veterinary

products.

1b4 Artwork (Mock-ups)

A mock-up is a flat artwork design in full color, presented so that, following cutting and

folding, where necessary, it provides a full size replica of both the outer and immediate

packaging so that the two dimensional presentation of the label text is clear. The application

for a marketing authorization must include one or more mock-ups of the outer packaging

and of the immediate packaging of the product. Refer to the Guidance for presenting the

SPC, PL, and labeling information for veterinary products.

1b5 Samples

A number of samples should provide to perform complete testing. The required quantities

of samples further described in the SFDA Guidance for Submission .The submitted

samples must represent the final finished product to be marketed in Saudi Arabia.

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1c Critical Summaries (CS)

1c1 Quality

1c2 Safety

1c3 Efficacy

The Quality, Safety, Efficacy Summary is a summary that follows the scope and the outline

of the Body of Data. The CS should not include information, data or justification that was

not already included in each part or other parts of the structure. The CS should include

sufficient information from each section to provide the reviewer with an overview of each

part. The CS should include a discussion of key issues that integrates information from

sections in the Quality, Safety, Efficacy part and supporting information from another part.

This CS normally should not exceed 40 pages of text, excluding tables and figures. For

biotech, products and products manufactured using processes that are more complex, the

document could be longer but normally should not exceed 80 pages of text (excluding

tables and figures). The use of tables to summarize the information is encouraged, where

possible.

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III. Data Requirements for Veterinary

Pharmaceutical Products

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Part 2 Quality Documentation

2a Qualitative and Quantitative Particulars

2a1 Qualitative Particulars

2a2 Usual Terminology

2a3 Quantitative Particulars

2a4 Development pharmaceutics


2b1 Manufacturer and Batch Formula

2b2 Description of the Manufacturing Process and Process Controls

2b3 Facility, Equipment, Controls of Critical Steps and Intermediates

2b4 Process Validation and/or Evaluation

2c Control of Starting Materials


2c2 Excipient(s)

2c3 Container / Closure System

2c4 Substances of Biological Origin

2d Control Tests at Intermediate Process Stages


2e1 Specifications of the Finished Product

2e2 General Characteristics of the Finished Product

2e3 Identification and Assay of Active Substance(s)

2e4 Identification and Assay of Excipient Components

2e5 Safety Tests

2f Stability Tests

2f1 Active Substances(s)

2f2 Finished Product

2g Other Information

Part 3 Safety and Residues Tests

3a Safety Tests

3a1 Precise Identification of the Product and of its Active Substance(s)

3a2 Pharmacology

3a3 Toxicology

3a4 Other Requirements

3a5 URA (User Safety)

3a6 ERA (Environmental Risk Assessment)

3b Residue tests

3b1 Introduction

3b2 Identification of Product

3b3 Metabolism and Residue Kinetics

3b4 Residue Analytical Method

Part 4 Preclinical and Clinical Trials

4a Preclinical Requirements

4a1 Pharmacology

4a2 Resistance

4a3 Target Animal Tolerance

4b Clinical Requirements

4b1 Clinical Trials

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Part 2 Quality Documentation

The pharmaceutical (physico-chemical, biological or microbiological) data shall include

for the active substance(s) and for the finished veterinary medicinal product information

on the manufacturing process, the characterization and properties, the quality control

procedures and requirements, the stability as well as a description of the composition, the

development and presentation of the veterinary medicinal product.

All test procedures shall fulfill the criteria for analysis and control of the quality of the

starting materials and the finished product. The results of the validation studies shall be

provided.



Qualitative particulars of all the constituents of the veterinary medicinal product shall mean

the designation or description of:

- the active substance (s),

- the constituent (s) of the excipients, whatever their nature or the quantity used,

including preservatives, adjuvants, stabilizers, thickeners, emulsifiers, coloring

matter, flavoring, aromatic substances

- the constituents, intended to be ingested or otherwise administered to animals, of

the outer covering of the veterinary medicinal products, such as capsules, gelatin

capsules.

These particulars shall be supplemented by any relevant data concerning the immediate

packaging and if relevant the secondary packaging and, where appropriate, its manner

of closure, together with details of devices with which the medicinal product will be

used or administered and which will be supplied with the medicinal product.


The usual terminology to be used in describing the constituents of the veterinary medicinal

product:

1. in respect of constituents which appear the Pharmacopoeia

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2. in respect of other constituents, the international non-proprietary name (INN)

recommended by the World Health Organization (WHO), which may be

accompanied by another non-proprietary name, or, failing these, the exact scientific

designation; constituents not having an international non-proprietary name or an

exact scientific designation shall be described by a statement of how and from what

they were prepared, supplemented, where appropriate, by any other relevant details,


In order to give the ‘quantitative particulars’ of all the active substances of the veterinary

medicinal products, it is necessary, depending on the pharmaceutical form concerned, to

specify the mass, or the number of units of biological activity, either per dosage-unit or per

unit of mass or volume, of each active substance.

Units of biological activity shall be used for substances, which cannot be defined

chemically. Where an International Unit of biological activity has been defined by the

WHO, this shall be used. Where no International Unit has been defined, the units of

biological activity shall be expressed in such a way as to provide unambiguous information

on the activity of the substances by using where applicable pharmacopoeia Units.

Whenever possible, biological activity per units of mass or volume shall be indicated. This

information shall be supplemented:

- in respect of single-dose preparations, by the mass or units of biological activity of

each active substance in the unit container, taking into account the usable volume

of the product, after reconstitution, where appropriate,

- in respect of veterinary medicinal products to be administered by drops, by the mass

or units of biological activity of each active substance contained per drop or

contained in the number of drops corresponding to 1 ml or 1 g of the preparation,

- in respect of syrups, emulsions, granular preparations and other pharmaceutical

forms to be administered in measured quantities, by the mass or units of biological

activity of each active substance per measured quantity.

- Active substances present in the form of compounds or derivatives shall be

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described quantitatively by their total mass, and if necessary or relevant, by the

mass of the active entity or entities of the molecule.

Active substances present in the form of compounds or derivatives shall be described

quantitatively by their total mass, and if necessary or relevant, by the mass of the active

entity or entities of the molecule.

2a4 Development Pharmaceutics

An explanation shall be provided with regard to the choice of composition, constituents,

immediate packaging, possible further packaging, outer packaging if relevant, the intended

function of the excipients in the finished product and the method of manufacture of the

finished product. This explanation shall be supported by scientific data on development

pharmaceutics. The overage, with justification thereof, shall be stated.

The microbiological characteristics (microbiological purity and antimicrobial activity) and

usage instructions shall be proven to be appropriate for the intended use of the veterinary

medicinal product as specified in the marketing authorization application dossier.


2b1 Manufacturer and Batch Formula

The name, address and responsibility of each manufacturer along with the Batch formula

information should be included.

Incase of using information from more than one manufacturer, the relation between both

manufacturers should be indicated.

2b2 Description of the Manufacturing Process and Process Controls

Each proposed production site or facility involved in manufacturing and testing shall be

indicated including at least the following:

- mention of the various stages of manufacture, so that an assessment can be made of

whether the processes employed in producing the pharmaceutical form might have

produced an adverse change in the constituents,

- in the case of continuous manufacture, full details concerning precautions taken to ensure the

homogeneity of the finished product,

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- the actual manufacturing formula, with the quantitative particulars of all the

substances used, the quantities of excipients, however, being given in approximate

terms insofar as the pharmaceutical form makes this necessary; mention shall be

made of any substances that may disappear in the course of manufacture; any overage

shall be indicated and justified.

- a statement of the stages of manufacture at which sampling is carried out for in-

process control tests and the limits applied, where other data in the documents

supporting the application show such tests to be necessary for the quality control of

the finished product.

2b3 Facility, Equipment, Controls of Critical Steps and Intermediates

All information regarding to Facility, Equipment, Controls of critical steps and

intermediates should be included.

2b4 Process Validation and/or Evaluation

Detailed information regarding to Process validation and/or evaluation should be indicated

including at least the following:

- experimental studies validating the manufacturing process and where appropriate a

process validation scheme for production scale batches,

- for sterile products, where non-pharmacopoeial standard sterilisation conditions are

used, details of the sterilisation processes and/or aseptic procedures used.

2c Control of Starting Materials

General Requirements

For the purposes of this paragraph, “starting materials” shall mean all the constituents of

the veterinary medicinal product and, if necessary, of its container including its closure as

mentioned in section 2a1.

The dossier shall include the specifications and information on the tests to be conducted

for quality control of all batches of starting materials.

The routine tests carried out on each batch of starting materials must be as stated in the

application for marketing authorization. If tests other than those mentioned in a

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pharmacopoeia are used, this shall be justified by providing proof that the starting materials

meet the quality requirements of that pharmacopoeia.

Certificates of Analysis shall be presented for the starting materials in order to demonstrate

compliance with the defined specification.

If the starting material is of vegetable origin, the monograph of the material should be

summarized (specification with description of the test procedures). Only the substances of

vegetable origin that determine the therapeutic activity of the product should be stated.


2c1.1 Detailed Requirements of the Active Substance (API)

The name, address, and responsibility of each manufacturer and each proposed production

site or facility involved in manufacturing and testing of an active substance shall be

indicated.

Other information to Precise identification of the active substance(s) should include the

following information:

- International non-proprietary name (INN),

- International Union of Pure and Applied Chemistry Name (IUPAC),

- Chemical Abstract Service (CAS) number,

- therapeutic, pharmacological and chemical classification,

- synonyms and abbreviations,

- structural formula,

- molecular formula,

- molecular weight,

- degradation and impurity,

- qualitative and quantitative composition of impurities,

- description of physical properties,

- melting point,

- boiling point,

- vapour pressure,

- solubility in water and organic solvents expressed in g/l, with indication of

temperature,

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- density,

- spectra of refraction, rotation, etc,

- formulation of the product.

For a well-defined active substance, the active substance manufacturer may arrange for

the following information:

1. A detailed description of the manufacturing process;

2. A description of the quality control during manufacture;

3. A description of the process validation.

In this case, the manufacturer shall however provide the applicant with all the data which

may be necessary for the latter to take responsibility for the veterinary medicinal product.

The manufacturer shall confirm in writing to the applicant that the shall ensure batch to

batch consistency and not modify the manufacturing process or specifications without

informing the applicant. Documents and particulars supporting the application for such a

change shall be supplied to the SFDA those documents and particulars shall also be

supplied to the applicant where they concern the applicant’s part of the Active Substance

Master File.

Additionally, information on the method of manufacture, on quality control and on

impurities as well as evidence of the molecular structure shall be provided where a

Certificate of Suitability for the active substance is not available:

1. Information on the manufacturing process shall include a description of the active

substance manufacturing process that represents the applicant’s commitment for

the manufacture of the active substance. All materials needed in order to

manufacture the active substance (s) shall be listed, identifying where each material

is used in the process. Information on the quality and control of those materials

shall be provided. Information demonstrating that materials meet standards which

are appropriate for their intended use shall be provided.

2. Information on quality control shall contain tests (including acceptance criteria)

carried out at every critical step, information on the quality and control of

intermediates and process validation and/or evaluation studies as appropriate. It

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shall also contain validation data for the analytical methods applied to the active

substance, where appropriate.

3. Information on impurities shall indicate predictable impurities together with the

levels and nature of observed impurities. It shall also contain information on the

safety of these impurities where relevant.

4. For biotechnological veterinary medicinal products, evidence of molecular

structure shall include the schematic amino acid sequence and relative molecular

mass.

2c1.2 Active Substances listed in Pharmacopeia

The general and specific monographs of the Pharmacopoeia shall be applicable to all active

substances appearing in it.

Constituents fulfilling the requirements of the Pharmacopoeia shall be deemed to comply

sufficiently with description of the testing methods employed by the manufacturer. In this

case, the description of the analytical methods and procedures shall be replaced in each

relevant section by an appropriate reference to the pharmacopoeia in question.

In cases where a specification contained in a monograph of the Pharmacopoeia is

insufficient to ensure the quality of the substance, SFDA may request more appropriate

specifications from the applicant, including limits for specific impurities with validated test

procedures.

2c1.3 Active Substances not in a Pharmacopeia

Specification and routine tests, the scientific data on nomenclature, description,

manufacture, quality control during manufacture, the development chemistry (including

evidence of structure, potential isomerism, physico-chemical characteristics and analytical

validation,) potential and actual impurities and the batch analysis should be submitted.

Constituents which are not given in any pharmacopoeia shall be described in the form of a

monograph under the following headings:

a) the name of the constituent , meeting the requirements composition section, shall

be supplemented by any trade or scientific synonyms;

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b) the definition of the substance, set down in a form similar to that used in

Pharmacopoeia, shall be accompanied by any necessary explanatory evidence,

especially concerning the molecular structure. Where substances can only be

described by their manufacturing method, the description shall be sufficiently

detailed to characterize a substance which is constant both on its composition and

in its effects;

c) methods of identification may be described in the form of complete techniques as

used for production of the substance, and in the form of tests which ought to be

carried out as a routine matter;

d) purity tests shall be described in relation to each individual predictable impurity,

especially those which may have a harmful effect, and, if necessary, those which,

having regard to the combination of substances to which the application refers,

might adversely affect the stability of the medicinal product or distort analytical

results;

e) tests and limits to control parameters relevant to the finished product, such as

particle size and sterility shall be described and methods shall be validated where

relevant;

f) with regard to complex substances of plant or animal origin, a distinction must be

made between the case where multiple pharmacological effects render chemical,

physical or biological control of the principal components necessary, and the case

of substances containing one or more groups of principles having similar activity,

in respect of which an overall method of assay may be accepted.

Those data shall demonstrate that the proposed set of test procedures is sufficient to control

the quality of the active substance from the defined source.

2c1.4 Physico-Chemical Characteristics Liable to Affect Bioavailability:

The following items of information concerning active substances, whether or not listed in

the pharmacopoeias, shall be provided as part of the general description of the active

substances if the bioavailability of the veterinary medicinal product depends on them:

- crystalline form and solubility coefficients,

- particle size, where appropriate after pulverisation,

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- state of hydration,

- oil/water coefficient of partition,

- pK/pH values.

Note: The first three indents are not applicable to substances used solely in solution.

For active substances of vegetable origin and preparations, Test for the potential

contaminant (micro-organisms, pesticides, fumigants, toxic metals, radioactivity etc.)

should be discussed.

2c2 Excipient(s)

Excipients shall comply with the requirements of the appropriate pharmacopoeia general

and specific monographs. Where appropriate, additional tests to control parameters such

as particle size, sterility, residual solvents shall supplement the requirements of the

monograph.

In the absence of a pharmacopoeial monograph, a specification shall be proposed and

justified. The requirements for specifications as set out for the active substance not in a

pharmacopeia shall be followed. The proposed methods and their supporting validation

data shall be presented.

For novel excipients, that is to say excipient(s) used for the first time in a veterinary

medicinal product or by a new route of administration, details of manufacture,

characterization, and controls, with cross references to supporting safety data, both clinical

and non-clinical, shall be provided.

2c3 Container Closure

2C3.1 Active Substance

Detailed information on the container-closure system for the active substance shall be

given. The level of information required shall be determined by the physical state (liquid,

solid) of the active substance.

2C3.2 Finished Product

Detailed information on the container-closure system for the finished product shall be

given. The level of information required shall be determined by the route of administration

of the veterinary medicinal product and the physical state (liquid, solid) of the dosage form.

29

Packaging materials shall comply with the requirements of the appropriate pharmacopoeia

monograph.

Scientific data on the choice and suitability of the packaging material shall be presented.

For novel packaging materials in contact with the product, information on their

composition, manufacture and safety shall be presented.

Specifications and, if appropriate, performance data shall be presented for any dosing or

administration device supplied with the veterinary medicinal product.

2c4 Substances of Biological Origin

The origin, including geographical region, and history of starting materials shall be

described and documented.

The description of the starting material shall include the manufacturing strategy,

purification/inactivation procedures with their validation and all in-process control

procedures designed to ensure the quality, safety and batch-to-batch consistency of the

finished product.

When cell banks are used, the cell characteristics shall be shown to have remained

unchanged at the passage level used for the production and beyond.

Seed materials, cell banks and pools of serum and, whenever possible, the source materials

from which they are derived shall be tested for extraneous agents.

When starting materials of animal or human origin are used, the measures used to ensure

freedom from potentially pathogenic agents shall be described.

If the presence of potentially pathogenic extraneous agents is inevitable, the material shall

be used only when further processing ensures their elimination and/or inactivation, and this

shall be validated.

Documentation shall be supplied to demonstrate that the seed materials, cell seeds, batches

of serum and other material originating from animal species relevant for the transmission

of TSE comply with the Note for Guidance on minimizing the risk of transmitting animal

spongiform encephalopathy agents via human and veterinary medicinal products, as well

as with the corresponding monograph of the European Pharmacopoeia. Certificates of

Suitability issued by the European Directorate for the Quality of Medicines and

30

HealthCare, with reference to the relevant monograph of the European Pharmacopoeia,

may be used to demonstrate compliance.

2d Control Tests at Intermediate Process Stages

The dossier shall include particulars relating to the product control tests that may be carried

out at an intermedia test age of the manufacturing process, with a view to ensuring the

consistency of the technical characteristics and the production process.

These tests are essential for checking the conformity of the veterinary medicinal product

with the formula when, exceptionally, an applicant proposes an analytical method for

testing the finished product which does not include the assay of all the active substances

(or of all the excipient components subject to the same requirements as the active

substances).

The same applies where the quality control of the finished product depends on in-process

control tests, particularly if the substance is essentially defined by its manufacturing

method.

Where an intermediate product may be stored prior to further processing or primary

assembly, a shelf life for the intermediate product shall be defined on the basis of the data

resulting from stability studies.


2e1 Specifications of the Finished Product

For the control of the finished product, a batch of a finished product comprises all the units

of a pharmaceutical form which are made from the same initial quantity of material and

have undergone the same series of manufacturing and/or sterilization operations or, in the

case of a continuous production process, all the units manufactured in a given period of

time. The test which are carried out routinely on each batch of finished product should be

specified. The frequency of the tests which are not carried out routinely shall be stated.

Release limits shall be indicated.

- Specifications of the medicinal product

31

Methods and Acceptance Limits

Characteristics of the medicinal product

up to the end of shelf life

of the medicinal product

at release

1. Characteristics of the

pharmaceutical form

Indicate with an asterisk the specification limits

which may require updating in the light of experience

acquired after the first “n” production batches

2. Identification and assay

of active substance

3. Purity tests

4. Excipient: Identification

for example of colorants,

preservatives, limit

values of preservatives

or antioxidants etc.

The dossier shall include particulars relating to control tests on the finished product at

release. They shall be submitted in accordance with the following requirements.

If test procedures and limits other than those mentioned in the relevant monographs and

general chapters of the Pharmacopoeias, this shall be justified by providing proof that the

finished product would, if tested in accordance with those monographs, meet the quality

requirements of that pharmacopoeia for the pharmaceutical form concerned.

For finished product specifications (Release and Shelf-life) should include the following

points:

- Name of the active pharmaceutical ingredient and Finished product.

- Specification/Version number and Effective date.

- Reference(s).

- A footnote including chemical names for all known impurities.

- Signature by the concerned individual(s).

2e2 General Characteristics of the Finished Product

Other information to Precise identification of Precise identification of the product and of

its active substance(s) should include the following information:

32

- International non-proprietary name (INN),



- Therapeutic, pharmacological and chemical classification,

- Synonyms and abbreviations,

- Structural formula,

- Molecular formula,

- Molecular weight,

- Degradation and impurity,

- Qualitative and quantitative composition of impurities,

- Description of physical properties,

- Melting point,

- Boiling point,

- Vapour pressure,

- Solubility in water and organic solvents expressed in g/l, with indication of

temperature,

- Density,

- Spectra of refraction, rotation, etc,

- Formulation of the product.

Certain tests of the general characteristics of a product shall always be included among the

tests on the finished product. These tests shall, wherever applicable, relate to the control of

average masses and maximum deviations, to mechanical, physical or microbiological tests,

organoleptic characteristics, physical characteristics such as density, pH, refractive index.

For each of these characteristics, standards and tolerance limits shall be specified by the

applicant in each particular case.

The conditions of the tests, where appropriate, the equipment/apparatus employed and the

standards shall be described in precise details whenever they are not given in the

pharmacopoeia.

Furthermore, solid pharmaceutical forms having to be administered orally shall be

subjected to in vitro studies on the liberation and dissolution rate of the active substance or

33

substances, unless otherwise justified.

2e3 Identification and Assay of Active Substance(s)

Detailed information on Validation of Analytical Procedures of active substance(s)

including Reference Standards or Materials should be included.

Identification and assay of the active substance(s) shall be carried out either in a

representative sample from the production batch or in a number of dosage units analyzed

individually.

Unless there is appropriate justification, the maximum acceptable deviation in the active

substance content of the finished product shall not exceed ± 5% at the time of manufacture.

On the basis of the stability tests, the manufacturer shall propose and justify maximum

acceptable deviation limits in the active substance content of the finished product up to the

end of the proposed shelf life.

It shall be supplemented by a method of quantitative evaluation, enabling the SFDA to

have the conformity of the medicinal product with its specification verified after it has

been placed on the market.

An in vivo or in vitro biological assay shall be obligatory when physico-chemical methods

cannot provide adequate information on the quality of the product. Such an assay shall,

whenever possible, include reference materials and statistical analysis allowing calculation

of confidence limits. Where these tests cannot be carried out on the finished product, they

may be performed at an intermediate stage, as late as possible in the manufacturing process.

Where degradation occurs during manufacture of the finished product, the maximum

acceptable levels of individual and total degradation products immediately following

manufacture shall be indicated.

Where the particulars given in section 2b show that a significant overage of an active

substance is employed in the manufacture of the medicinal product or where the stability

data show that the assay of the active substance declines on storage, the description of the

control tests on the finished product shall include, where appropriate, the chemical and, if

necessary, the toxico-pharmacological investigation of the changes that this substance has

undergone, and possibly the characterization and/or assay of the degradation products.

34


Detailed information on Validation of Analytical Procedures of excipient including

Reference Standards or Materials should be included.

An identification test and an upper and lower limit test shall be obligatory for each

individual antimicrobiological preservative and for any excipient that is liable to affect the

bioavailability of the active substance, unless the bioavailability is guaranteed by other

appropriate tests. An identification test and an upper limit test shall be obligatory for any

antioxidant and for any excipient liable to adversely affect physiological functions, with a

lower limit test also included for antioxidants at time of release.

2e5 Safety Tests

Apart from the toxico-pharmacological tests submitted with the application for marketing

authorization, particulars of safety tests, such as sterility and bacterial endotoxins, shall be

included in the analytical particulars wherever such tests must be undertaken as a matter of

routine in order to verify the quality of the product.

2f Stability Tests

Refer to the VICH stability testing guidelines:

http://www.vichsec.org/guidelines/pharmaceuticals/pharma-quality/pharma-stability.html

Moreover, certain SFDA stability testing guidelines been established and are under review

by the SFDA standard setting departments and will be published as soon as possible.

2f1 Active Substance

Full Stability data including accelerated and long term stability studies shall be presented

to support the defined retest period and storage conditions. The type of stability studies

conducted, protocols used, the analytical procedures used and their validation together with

the detailed results shall be presented. The stability commitment with a summary of the

protocol shall be provided.

2f2 Finished Product

Full Stability data including accelerated and long term stability studies along with in-use

stability study and stability after reconstitution, if applicable, should be submitted.

http://www.vichsec.org/guidelines/pharmaceuticals/pharma-quality/pharma-stability.html

35

A description shall be given of the investigations by which the shelf life, the recommended

storage conditions and the specifications at the end of the shelf life proposed by the

applicant have been determined.

The type of stability studies conducted, protocols used, the analytical procedures used and

their validation together with the detailed results shall be presented.

Where a finished product requires reconstitution or dilution prior to administration, details

of the proposed shelf life and specification for the reconstituted/diluted product are

required, supported by relevant stability data.

In the case of multi-dose containers, where relevant, stability data shall be presented to

justify a shelf life for the product after it has been broached for the first time and an in-use

specification shall be defined.

Where a finished product is liable to give rise to degradation products, the applicant shall

declare and indicate the identification methods and test procedures for degradation

products.

The conclusions shall contain the results of analyses, justifying the proposed shelf life and

if appropriate, the in-use shelf life, under the recommended storage conditions and the

specifications of the finished product at the end of the shelf life, and in-use shelf life if

appropriate, of the finished product under these recommended storage conditions.

The maximum acceptable level of individual and total degradation products at the end of

shelf life shall be indicated.

A study of the interaction between product and container shall be submitted wherever the

risk of such interaction is regarded as possible, especially where injectable preparations are

concerned.

The stability commitment with a summary of the protocol shall be provided.

2g Other Related Documents

This part is intended for a summary of any information relevant to the pharmaceutical

assessment and which has not been covered by any of the previous report. Information

on the analytical test procedures used in the metabolism and bioavailability studies and

their validation, and a summary of the synthesis of radiolabeled active substance used

in metabolic and/or pharmacokinetic studies should be provided.

36

Part 3 Safety and Residues Tests

Part 3 of the dossier is aimed at demonstrating the potential risks for man and the

environment resulting from use of the product. In the context of human safety, it is

necessary to consider possible effects on people using the product, handling treated animals

and consuming food products derived from treated animals. Although a knowledge of

adverse effects in the target species may be useful additional information when assessing

the risk for man and the environment, Part 3 is not primarily concerned with target species

safety, which should be considered in detail in Part 4 of the dossier.

Studies submitted to demonstrate safety of chemicals to man and the environment must be

conducted and reported in accordance with Good Laboratory Practice (GLP).

3a Safety Tests

Safety Documentation:

Relevant data obtained from the open literature should always be included in the

documentation. Copies of published data should be appended to the proprietary data. All

proprietary data should be discussed in conjunction with the data from the open literature.

Residue Documentation:

Documents should be presented as dated and signed reports from named laboratories.

Summaries not accompanied by the individual data will not be accepted as valid

documentation.

Relevant data obtained from the open literature should always be included in the

documentation. Copies of published data should be appended to the proprietary data. All

proprietary data should be discussed in conjunction with the data from the open literature.

The safety documentation shall show:

a) the potential toxicity of the veterinary medicinal product and any dangerous or

undesirable effects which may occur under the proposed conditions of use in

animals; these should be evaluated in relation to the severity of the pathological

condition concerned;

37

b) the potential harmful effects to man of residues of the veterinary medicinal product

or substance in foodstuffs obtained from treated animals and what difficulties these

residues may create in the industrial processing of foodstuffs;

c) the potential risks which may result from the exposure of human beings to the

veterinary medicinal product, for example during its administration to the animal;

d) the potential risks for the environment resulting from the use of the veterinary

medicinal product.

All results shall be reliable and valid generally. Whenever appropriate, mathematical and

statistical procedures shall be used in designing the experimental methods and in evaluating

the results. Additionally, information shall be provided regarding the therapeutic potential

of the product and about the hazards connected with its use.

In some cases, it may be necessary to test the metabolites of the parent compound where

these represent the residues of concern.

An excipient used in the pharmaceutical field for the first time shall be treated like an active

substance.

3a1 Precise Identification of the Product and of its Active Substance(s)

- international non-proprietary name (INN),



- therapeutic, pharmacological and chemical classification,

- synonyms and abbreviations,

- structural formula,

- molecular formula,

- molecular weight,

- degree of impurity,

- qualitative and quantitative composition of impurities,

- description of physical properties,

- melting point,

- boiling point,

38

- vapour pressure,

- solubility in water and organic solvents expressed in g/l, with indication of

temperature,

- density,

- spectra of refraction, rotation, etc,

- formulation of the product.

3a2 Pharmacology

Pharmacological studies are of fundamental importance in clarifying the mechanisms by

which the veterinary medicinal product produces its therapeutic effects and therefore

pharmacological studies conducted in experimental and target species of animal shall be

included in part 4.

However, pharmacological studies may also assist in the understanding of toxicological

phenomena. Moreover, where a veterinary medicinal product produces pharmacological

effects in the absence of a toxic response, or at doses lower than those required to elicit

toxicity, these pharmacological effects shall be taken into account during the evaluation of

the safety of the veterinary medicinal product.

Therefore, the safety documentation shall always be preceded by details of

pharmacological investigations undertaken in laboratory animals and all relevant

information observed during clinical studies in the target animal.

3a2.1 Pharmacodynamics

Information on the mechanism of action of the active substance(s) shall be provided,

together with information on primary and secondary pharmacodynamics effects in order to

assist in the understanding of any adverse effects in the animal studies.

3a2.1 Pharmacokinetics

Data on the fate of the active substance and its metabolites in the species used in the

toxicological studies shall be provided, covering absorption, distribution, metabolism and

excretion (ADME). The data shall be related to the dose/effect findings in the

pharmacological and toxicological studies, to determine adequate exposure. Comparison

with the pharmacokinetic data obtained in the studies on the target species, section 4a2,

39

shall be included in order to determine the relevance of the results obtained in the

toxicology studies for the toxicity to the target species.

3a3 Toxicology

The documentation on toxicology includes:

1. basic tests required for all new veterinary medicinal products for use in food-

producing animals in order to assess the safety of any residues present in food for

human consumption;

2. additional tests that may be required depending on specific toxicological concerns

such as those associated with the structure, class and mode of action of the active

substance(s);

3. special tests which might assist in the interpretation of data obtained in the basic or

additional tests.

The studies shall be conducted with the active substance(s), not with the formulated

product. Where studies of the formulated product are required, this is specified in the below

sections:

3a3.1 Single – Dose Toxicity

Single-dose toxicity studies may be used to predict:

- the possible effects of acute over dosage in the target species,

- the possible effects of accidental administration to humans,

- the doses which may usefully be employed in the repeat dose studies.

Single-dose toxicity studies should reveal the acute toxic effects of the substance and the

time course for their onset and remission.

The studies to be carried out shall be selected with a view to providing information on user

safety, e.g. if substantial exposure by inhalation or dermal contact of the user of the

veterinary medicinal product is anticipated, those routes of exposure shall be studied.

3a3.2 Repeat-Dose Toxicity

Repeat-dose toxicity tests are intended to reveal any physiological and/or pathological

changes induced by repeated administration of the active substance or combination of

40

active substances under examination, and to determine how these changes are related to

dosage.

In the case of pharmacologically active substances or veterinary medicinal products

intended solely for use in non-food-producing animals, a repeat-dose toxicity study in one

species of experimental animal shall normally be sufficient. This study may be replaced by

a study conducted in the target animal. The frequency and route of administration, and the

duration of the study shall be chosen having regard to the proposed conditions of clinical

use. The investigator shall give his reasons for the extent and duration of the trials and the

dosages chosen.

In the case of substances or veterinary medicinal products intended for use in food-

producing animals, repeat-dose (90 day) toxicity testing shall be performed in a rodent and

a non-rodent species in order to identify target organs and toxicological endpoints and

identify the appropriate species and the dose levels to be used in chronic toxicity testing, if

appropriate.

The investigator shall give his reasons for the choice of species, having regard to the

available knowledge of the metabolism of the product in animals and man. The test

substance shall be administered orally. The investigator shall clearly state and give his

reasons for the method and frequency of administration and the length of the trials.

The maximum dose should normally be selected so as to bring harmful effects to light. The

lowest dose level should not produce any evidence of toxicity.

Evaluation of the toxic effects shall be based on observation of behavior, growth,

hematology and physiological tests, especially those relating to the excretory organs, and

also on autopsy reports and accompanying histological data. The choice and range of each

group of tests depends on the species of animal used and the state of scientific knowledge

at the time.

In the case of new combinations of known substances which have been investigated in

accordance with this guidance, the repeat-dose tests may, except where toxicity tests have

demonstrated potentiation or novel toxic effects, be suitably modified by the investigator,

who shall submit his reasons for such modifications.

41

3a3.3 Tolerance in the Target Species

A summary shall be provided of any signs of intolerance which have been observed during

studies conducted, usually with the final formulation, in the target species in accordance

with the requirements of Section 4a3. The studies concerned, the dosages at which the

intolerance occurred and the species and breeds concerned shall be identified.

Details of any unexpected physiological changes shall also be provided. The full reports of

these studies shall be included in part 4.

3a3.4 Reproductive Toxicity including Developmental Toxicity

3a3.4.1 Study of the Effects on Reproduction

The purpose of this study is to identify possible impairment of male or female reproductive

function or harmful effects on progeny resulting from the administration of the veterinary

medicinal products or substance under investigation.


intended for use in food-producing animals, the study of the effects on reproduction shall

be performed in the form of a multi-generation reproduction study, designed to detect any

effect on mammalian reproduction. These include effects on male and female fertility,

mating, conception, implantation, ability to maintain pregnancy to term, parturition,

lactation, survival, growth and development of the offspring from birth through to weaning,

sexual maturity and the subsequent reproductive function of the offspring as adults. At least

three dose levels shall be used. The maximum dose should be selected so as to bring

harmful effects to light. The lowest dose level should not produce any evidence of toxicity.

3a3.4.1 Study of Developmental Toxicity


intended for use in food-producing animals, tests on developmental toxicity shall be

performed. These tests shall be designed to detect any adverse effects on the pregnant

female and development of the embryo and foetus consequent to exposure of the female

from implantation through gestation to the day before predicted birth. Such adverse effects

42

include enhanced toxicity relative to that observed in non-pregnant females, embryo-foetal

death, altered foetal growth, and structural changes to the foetus.

A developmental toxicity test in the rat is required. Depending on the results, a study in a

second species may have to be performed.

In the case of pharmacologically active substances or veterinary medicinal products not

intended for use in food producing animals, a study of developmental toxicity shall be

performed in at least one species, which may be the target species, if the product is intended

for use in female animals which may be used for breeding. However, where the use of the

veterinary medicinal product would result in significant exposure to users, standard

developmental toxicity studies shall be performed.

3a3.5 Genotoxicity

Tests for genotoxic potential shall be performed to reveal changes which a substance may

cause in the genetic material of cells. Any substance intended to be included in a veterinary

medicinal product for the first time must be assessed for genotoxic properties.

3a3.6 Carcinogenicity

The decision on whether carcinogenicity testing is required shall take into account the

results of genotoxicity tests, structure-activity relationships and the findings in systemic

toxicity tests that may be relevant to neoplastic lesions in longer term studies.

Any known species specificity of the mechanism of toxicity shall be considered, as well as

any differences in metabolism between the test species, target animal species, and human

beings.

3a3.7 Exceptions

Where a veterinary medicinal product is intended for topical use, systemic absorption shall

be investigated in the target animal species. If it is proved that systemic absorption is

negligible, the repeated dose toxicity tests, the tests for reproductive toxicity and the

carcinogenicity tests may be omitted, unless:

- under the intended conditions of use laid down, oral ingestion of the veterinary

medicinal product by the animal is to be expected, or

43

- under the intended conditions of use laid down, exposure of the user of the

veterinary medicinal product by other routes than the dermal route is to be expected,

or

- the active substance or metabolites may enter foodstuffs obtained from the treated

animal.

3a4 Other Requirements

3a4.1 Special Studies

For particular groups of substances or if the effects observed during repeated dose studies

in animals include changes indicative of e.g. immunotoxicity, neurotoxicity- or, endocrine

dysfunction, further testing shall be required, e.g. sensitization studies or delayed

neurotoxicity tests. Depending on the nature of the product, it may be necessary to conduct

additional studies to assess the underlying mechanism of the toxic effect or the irritation

potential. Such studies shall usually be conducted with the final formulation.

The state of scientific knowledge shall be taken into account when designing such studies

and evaluating their results.

3a4.2 Microbiological Properties of Residues

o Potential Effects on the Microorganisms used for Industrial Food Processing

In certain cases, it may be necessary to carry out tests to determine whether

microbiologically active residues may interfere in technological processes in the industrial

processing of foodstuff.

3a4.3 Observations in Humans

Information shall be provided showing whether the pharmacologically active substances

of the veterinary medicinal product are used as medicinal products in human therapy; if

this is so, a compilation shall be made of all the effects observed (including adverse

reactions) in humans and of their cause, to the extent that they may be important for the

assessment of the safety of the veterinary medicinal product, where appropriate including

results from published studies; where constituents of the veterinary medicinal products are

themselves not used or are no longer used as medicinal products in human therapy, the

reasons shall be stated.

44

3a4.4 Development of Resistance

Data on the potential emergence of resistant bacteria of relevance for human health are

necessary in the case of veterinary medicinal products. The mechanism of the development

of such resistance is particularly important in this regard. Where necessary, measures to

limit resistance development from the intended use of the veterinary medicinal product

shall be proposed.

Resistance relevant for clinical use of the product shall be addressed in accordance with

part 4. Where relevant, cross reference shall be made to the data set out in part 4.

3a5 User Safety (URA)

This section shall include a discussion of the effects found in the preceding sections and

relate this to the type and extent of human exposure to the product with a view to

formulating appropriate user warnings and other risk management measures.

3a6 Environmental Risk Assessment (ERA)

3a6.1 Environmental Risk Assessment of Veterinary Medicinal Products not

containing or Consisting of Genetically Modified Organisms

An environmental risk assessment shall be performed to assess the potential harmful

effects, which the use of the veterinary medicinal product may cause to the environment

and to identify the risk of such effects. The assessment shall also identify any precautionary

measures which may be necessary to reduce such risk.

This assessment shall normally be conducted in two phases. The first phase of the

assessment shall always be performed.

The details of the assessment shall be provided in accordance with accepted guidance. It

shall indicate the potential exposure of the environment to the product and the level of risk

associated with any such exposure taking into account in particular the following items:

- the target animal species, and the proposed pattern of use,

- the method of administration, in particular the likely extent to which the product

will enter directly into environmental systems,

45

- the possible excretion of the product, its active substances or relevant metabolites

into the environment by treated animals; persistence in such excreta,

- the disposal of unused veterinary medicinal product or other waste product.

In the second phase, further specific investigation of the fate and effects of the product on

particular ecosystems shall be conducted. The extent of exposure of the product to the

environment, and the available information about the physical/chemical, pharmacological

and/or toxicological properties of the substance(s) concerned, including metabolites in case

of an identified risk, which has been obtained during the conduct of the other tests and

trials required by this guidance, shall be taken into consideration.

3a6.2 Environmental Risk Assessment for Veterinary Medicinal Products Containing

or Consisting of Genetically Modified Organisms

In the case of veterinary medicinal products containing or consisting of genetically

modified organisms the application shall also be accompanied by the documents required

by international guidance and describes the format in which the particulars relevant to the

environmental risk assessment.

3a6.3 Presentation of Particulars and Documents

The dossier of safety tests shall include the following:

- An index of all studies included in the dossier, a statement confirming that all data

known by the applicant at the time of submission, whether favourable or

unfavourable, are included,

- A justification for the omission of any type of study,

- An explanation of the inclusion of an alternative type of study,

- a discussion of the contribution that any study that pre-dates studies performed in

line with good laboratory practice (GLP).

Each study report shall include:

- A copy of the study plan (Protocol),

- A statement of compliance with good laboratory practice, where applicable,

- A description of the methods, apparatus and materials used,

- A description and justification of the test system,

46

- A description of the results obtained, in sufficient detail to allow the results to be

critically evaluated independently of their interpretation by the author,

- A statistical analysis of the results where appropriate,

- A discussion of the results, with comment on observed and no-observed-effect

levels, and on any unusual findings,

- A detailed description and a thorough discussion of the results of the study of the

safety profile of the active substance, and its relevance for the evaluation of

potential risks presented by residues to humans.

3b Residue Tests

3b1 Introduction

The purpose of studying the depletion of residues from the edible tissues or of eggs, milk

and honey derived from treated animals is to determine under what conditions and to what

extent residues may persist in foodstuffs produced from these animals. In addition, the

studies shall enable the determination of a withdrawal period.

In the case of veterinary medicinal products intended for use in food-producing animals,

the residue documentation shall show:

1. to what extent, and how long, do residues of the veterinary medicinal product or its

metabolites persist in the edible tissues of the treated animal or in milk, eggs and/or

honey obtained therefrom;

2. that in order to prevent any risk to the health of the consumer of foodstuffs from

treated animals, or difficulties in the industrial processing of foodstuffs, it is

possible to establish realistic withdrawal periods which can be observed under

practical farming conditions;

3. that the analytical method(s) used in the residues depletion study are sufficiently

validated to provide the necessary reassurance that the residues data submitted are

suitable as the basis for a withdrawal period.

3b2 Identification of Product

An identification of the veterinary medicinal product(s) used in the testing shall be

provided, including:

- composition,

47

- the physical and chemical (potency and purity) test results for the relevant

batch(es),

- batch identification,

- relationship to the final product,

- specific activity and radio-purity of labelled substances,

- position of labelled atoms in the molecule.

The dossier of residue tests shall include:

- an index of all studies included in the dossier,

- a statement confirming that all data known by the applicant at the time of

submission, whether favourable or unfavourable, are included,

- a justification for the omission of any type of study,

- an explanation of the inclusion of an alternative type of study,

- a discussion of the contribution that any study that pre-dates GLP can make to

the overall risk assessment,

- a withdrawal period proposal.

Each study report shall include:

- a copy of the study plan (Protocol),

- a statement of compliance with good laboratory practice, where applicable,

- a description of the methods, apparatus and materials used,

- a description of the results obtained, in sufficient detail to allow the results to be

critically evaluated independently of

- their interpretation by the author,

- a statistical analysis of the results where appropriate,

- a discussion of the results,

- an objective discussion of the results obtained, and proposals concerning the

withdrawal periods necessary to ensure that no residues which might constitute a

hazard for consumers are present in foodstuffs obtained from treated animals.

3b3 Metabolism and Residue Kinetics

48

3b3.1 Pharmacokinetics (Absorption, Distribution, Metabolism, Excretion)

A summary of the pharmacokinetic data shall be submitted with cross reference to the

pharmacokinetic studies in target species submitted in Part 4. The full study report does

not need to be submitted.

The purpose of pharmacokinetic studies with respect to residues of veterinary medicinal

products is to evaluate the absorption, distribution, metabolism and excretion of the product

in the target species.

The final product, or a formulation, which has comparable characteristics in terms of

bioavailability as the final product, shall be administered to the target animal species at the

maximum recommended dose.

Having regard to the method of administration, the extent of absorption of the veterinary

medicinal product shall be fully described. If it is demonstrated that systemic absorption of

products for topical application is negligible, further residue studies will not be required.

The distribution of the veterinary medicinal product in the target animal shall be described;

the possibility of plasma protein binding or passage into milk or eggs and of the

accumulation of lipophilic compounds shall be considered.

The pathways for the excretion of the product from the target animal shall be described.

The major metabolites shall be identified and characterized.

3b3.2 Depletion of Residues

The purpose of these studies, which measure the rate at which residues deplete in the target

animal after the last administration of the medicinal product, is to permit the determination

of withdrawal periods.

At a sufficient number of times after the test animal has received the final dose of the

veterinary medicinal product, the quantities of residues present shall be determined by

validated analytical methods; the technical procedures and the reliability and sensitivity of

the methods employed shall be specified.

3b4 Residue analytical method

49

The analytical method(s) used in the residues depletion study (studies) and its (their)

validation shall be described in detail.

The following characteristics shall be described:

- specificity,

- accuracy,

- precision,

- limit of detection,

- limit of quantification,

- practicability and applicability under normal laboratory conditions,

- susceptibility to interference,

- stability of incurred residues.

The suitability of the analytical method proposed shall be evaluated in the light of the state

of scientific and technical knowledge at the time the application is submitted.

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Part 4 Preclinical and clinical trials

A written summary is essential for large, complex clinical documentation. Such

documentation may be contained in numerous volumes, and a 1-2 page summary at the

beginning of each volume, which details its contents and includes an index of that volume,

is particularly helpful. These short summaries can then form the basis for the overall

summary.

4a Pre-clinical Requirements

Pre-clinical studies are required to establish the pharmacological activity and the tolerance

of the product.

4a1 Pharmacology

4a1.1 Pharmacodynamics

The pharmacodynamics effects of the active substance(s) included in the veterinary

medicinal product shall be characterized.

First, the mechanism of action and the pharmacological effects on which the recommended

application in practice is based shall be adequately described. The results shall be expressed

in quantitative terms (using, for example, dose-effect curves, time-effect curves, etc.) and,

wherever possible, in comparison with a substance the activity of which is well known.

Where a higher efficacy is being claimed for an active substance, the difference shall be

demonstrated and shown to be statistically significant.

Secondly, an overall pharmacological assessment of the active substance shall be provided,

with special reference to the possibility of secondary pharmacological effects. In general,

the effects on the main body functions shall be investigated.

Any effect of the other characteristics of the products (such as the route of administration

or formulation) on the pharmacological activity of the active substance shall be

investigated.

The investigations shall be intensified where the recommended dose approaches a dose

likely to produce adverse reactions.

The experimental techniques, unless they are standard procedures, shall be described in

51

such detail as to allow them to be reproduced, and the investigator shall establish their

validity. The experimental results shall be set out clearly and, for certain types of tests,

their statistical significance quoted.

Unless good reasons are given to the contrary, any quantitative modification of responses

resulting from repeated administration of the substance shall also be investigated.

Fixed combinations may be prompted either on pharmacological grounds or by clinical

indications. In the first case, the pharmacodynamics and/or pharmacokinetic studies shall

demonstrate those interactions, which might make the combination itself of value in

clinical use. In the second case, where scientific justification for the medicinal combination

is sought through clinical experimentation, the investigation shall determine whether the

effects expected from the combination can be demonstrated in animals and, at least, the

importance of any adverse reactions shall be checked. If a combination includes a new

active substance, the latter shall have been previously studied in depth.

4a2 Resistance

Where relevant, data on the potential emergence of resistant organisms of clinical relevance

are necessary for veterinary medicinal products. The mechanism of the development of

such resistance is particularly important in this regard.

Measures to limit resistance development from the intended use of the veterinary medicinal

product shall be proposed by the applicant.

Where relevant, cross reference shall be made to data set out in part 3.

4a2.1 Pharmacokinetics

Basic pharmacokinetic data concerning a new active substance are required in the context

of assessment of the clinical safety and efficacy of the veterinary medicinal product.

The objectives of pharmacokinetic studies in the target animal species can be divided into

three main areas:

1. descriptive pharmacokinetics leading to the determination of basic parameters;

52

2. use of these parameters to investigate the relationships between dosage regimen,

plasma and tissue concentration over time and pharmacological, therapeutic or

toxic effects;

3. where appropriate, to compare the kinetics between different target species and to

explore possible species differences having an impact on target animal safety and

efficacy of the veterinary medicinal product.

In the target animal species, pharmacokinetic studies are, as a rule, necessary as a

complement to the pharmacodynamics studies to support the establishment of effective

dosage regimens (route and site of administration, dose, dosing interval, number of

administrations, etc.). Additional pharmacokinetic studies may be required to establish

dosage regimens according to certain population variables.

Where pharmacokinetic studies have been submitted under Part 3 cross reference to such

studies may be made.

In the case of new combinations of known substances which have been investigated in

accordance with this guidance, pharmacokinetic studies of the fixed combination are not

required if it can be justified that the administration of the active substances as a fixed

combination does not change their pharmacokinetic properties.

Appropriate bioavailability studies shall be undertaken to establish bioequivalence:

- when comparing a reformulated veterinary medicinal product with the existing one,

- where necessary for the comparison of a new method or route of administration

with an established one.

4a3 Target Animal Tolerance

The local and systemic tolerance of the veterinary medicinal product shall be investigated

in the target animal species. The purpose of these studies is to characterize signs of

intolerance and to establish an adequate margin of safety using the recommended route(s)

of administration. This may be achieved by increasing the therapeutic dose and/or the

duration of treatment. The report on the trials shall contain details of all expected

pharmacological effects and all adverse reactions.

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4b Clinical Requirements

4b1 Clinical Trials

The purpose of clinical trials is to demonstrate or substantiate the effect of the veterinary

medicinal product after administration at the proposed dosage regimen via the proposed

route of administration and to specify its indications and contra-indications according to

species, age, breed and sex, its directions for use as well as any adverse reactions which it

may have.

Experimental data shall be confirmed by data obtained under normal field conditions.

Unless justified, clinical trials shall be carried out with control animals (controlled clinical

trials). The efficacy results obtained should be compared with those from the target animal

species that have received a veterinary medicinal product authorized in the SFDA for the

same indications for use in the same target animal species, or a placebo or no treatment.

All the results obtained, whether positive or negative, shall be reported.

Established statistical principles shall be used in protocol design, analysis and evaluation

of clinical trials, unless justified.

4b1.1 Conduct of Clinical Trials

All veterinary clinical trials shall be conducted in accordance with a detailed trial protocol.

Clinical field trials shall be conducted in accordance with established principles of good

clinical practice, unless otherwise justified.

Before the commencement of any field trial, the informed consent of the owner of the

animals to be used in the trial shall be obtained and documented. In particular, the animal

owner shall be informed in writing of the consequences of participation in the trial for the

subsequent disposal of treated animals or for the taking of foodstuffs from treated animals.

A copy of this notification, countersigned and dated by the animal owner, shall be included

in the trial documentation.

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4b1.2 Particulars and Documents

The dossier on efficacy shall include all pre-clinical and clinical documentation and/or

results of trials, whether favorable or unfavorable to the veterinary medicinal products, in

order to enable an objective overall assessment of the risk/benefit balance of the product.

4b1.2.1 Results of Pre-clinical Trials

Wherever possible, particulars shall be given of the results of:

a) Tests demonstrating pharmacological actions;

b) Tests demonstrating the pharmacodynamics mechanisms underlying the

therapeutic effect;

c) Tests demonstrating the main pharmacokinetic profile;

d) Tests demonstrating target animal safety;

e) Tests investigating resistance.

f) Should unexpected results occur during the course of the tests, these should be

detailed.

Additionally, the following particulars shall be provided in all pre-clinical studies:

a) A summary;

a) A detailed experimental protocol giving a description of the methods, apparatus and

materials used, details such as species, age, weight, sex, number, breed or strain of

animals, identification of animals, dose, route and schedule of administration;

b) a statistical analysis of the results, where relevant;

c) An objective discussion of the results obtained, leading to conclusions on the

efficacy and safety of the veterinary medicinal product.

Total or partial omission of any of these data shall be justified.

4b1.2.2 Results of Clinical Trials

All the particulars shall be supplied by each of the investigators on individual record sheets

in the case of individual treatment and collective record sheets in the case of collective

treatment.

55

The particulars supplied shall take the following form:

a) Name, address, function and qualifications of investigator in charge;

b) Place and date of treatment; name and address of owner of the animals;

c) Details of the clinical trial protocol giving a description of the methods used,

including methods of randomisation and blinding, details such as the route of

administration, schedule of administration, the dose, identification of trial animals,

species, breeds or strains, age, weight, sex, physiological status;

d) Method of animal management and feeding, stating the composition of the feed and

the nature and quantity of any feed additives;

e) Case history (as full as possible), including occurrence and course of any

intercurrent diseases;

f) Diagnosis and means used to make it;

g) Clinical signs, if possible according to conventional criteria;

h) Precise identification of the formulation of the veterinary medicinal product used

in the clinical trial and the physical and chemical test results for the relevant

batch(es);

i) Dosage of the veterinary medicinal product, method, route and frequency of

administration and precautions, if any, taken during administration (duration of

injection, etc.);

j) Duration of treatment and period of subsequent observation;

k) All details concerning other veterinary medicinal products which have been

administered during the period of examination, either prior to or concurrently with

the test product and, in the latter case, details of any interactions observed;

l) All results of the clinical trials, fully describing the results based on the efficacy

criteria and end points specified in the clinical trial protocol and including the

results of the statistical analyses, if appropriate;

m) All particulars of any unintended event, whether harmful or not, and of any

measures taken in consequence; the cause-and-effect relationship shall be

investigated if possible;

n) Effect on animals’ performance if appropriate;

56

o) Effects on the quality of foodstuffs obtained from treated animals, particularly in

the case of veterinary medicinal products intended for use as performance

enhancers;

p) A conclusion on the safety and efficacy in each individual case or, summarized in

terms of frequencies or other appropriate variables where specific mass treatment

is concerned.

Omission of one or more items (a) to (p) shall be justified.

In respect of each clinical trial, the clinical observations shall be summarized in a synopsis

of the trials and the results thereof, indicating in particular:

a) The number of control and test animals treated either individually or collectively,

with a breakdown according to species, breed or strain, age and sex;

b) The number of animals withdrawn prematurely from the trials and the reasons for

such withdrawal;

c) In the case of control animals, whether they have:

- received no treatment, or

- received a placebo, or

- received the same active substance under investigation in a different formulation or

by a different route;

d) The frequency of observed adverse reactions;

e) Observations as to the effect on animal performance, if appropriate;

f) Details concerning test animals which may be at increased risk owing to their age,

their mode of rearing or feeding, or the purpose for which they are intended, or

animals the physiological or pathological condition of which requires special

consideration;

g) A statistical evaluation of the results.

Finally, the investigator shall draw general conclusions on the efficacy and safety of the

veterinary medicinal product under the proposed conditions of use, and in particular any

57

information relating to indications and contraindications, dosage and average duration of

treatment and where, appropriate, any interactions observed with other veterinary

medicinal products or feed additives as well as any special precautions to be taken during

treatment and the clinical symptoms of over dosage, when observed.

In the case of fixed combination products, the investigator shall also draw conclusions

concerning the safety and the efficacy of the product when compared with the separate

administration of the active substances involved.

58

IV. Data Requirements for Veterinary

Immunological Products

59


Part 2

Quality Documentation

2a Quantitative and Qualitative Particulars




2a4 Product Development


2c Production and Control of Starting Materials

2c1 Starting Materials listed in Pharmacopeias

2c2 Starting Materials not listed in Pharmacopeias

2d Control Tests during the Manufacture Process

2e Control Tests on the Finished Product

2e1 General Characteristics

2e2 Identification of Active Substance(s)

2e3 Batch Titre or Potency

2e4 Identification and Assay of Adjuvants

2e5 Identification and Assay of Excipients Components

2e6 Safety Tests

2e7 Sterility and Purity Test

2e8 Residual Humidity

2e9 Inactivation

2f Batch to Batch Consistency

2g Stability Tests

2h Other Information

Part 3

Safety Documentation

3a General Requirements

3b Laboratory Tests

3b1

Safety of One Dose

3b2

Safety of an Overdose

3b3 Safety of the Repeated Administration of One Dose

3b4 Examination of Reproductive Performance

3b5

Examination of Immunological Functions

3b6 Special Requirements for Live Vaccines

3b7 User Safety (URA)

3b8 Study of Residues

3b9 Interactions

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3c Field Studies

3d ERA (Environmental Risk Assessment)

3e Assessment of Products Containing or Consisting of GMOs

Part 4

Efficacy Documentation

4a General Principles

4b Performance of Trials

4c General Requirements

4d Laboratory Trials

4e Field Trials

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Part 2 Quality Documentations

All test procedures shall fulfil the necessary criteria for analysis and control of the quality

of the starting materials and the finished product and shall be validated procedures. The

results of the validation studies shall be provided. Any special apparatus and equipment

which may be used shall be described in adequate detail, possibly accompanied by a

diagram. The formulae of the laboratory reagents shall be supplemented, if necessary, by

the manufacturing method.

In the case of test procedures included in the Pharmacopoeias, this description may be

replaced by a detailed reference to the pharmacopoeia in question.

Where available, chemical and biological reference material of the Pharmacopoeia shall be

used. If other reference preparations and standards are used, they shall be identified and

described in detail.



Qualitative particulars of all the constituents of the immunological veterinary medicinal

product shall mean the designation or description of:

- the active substance(s),

- the constituents of the adjuvants,

- the constituent (s) of the excipients, whatever their nature or the quantity used,

including preservatives, stabilisers, emulsifiers, colouring matter, flavouring,

aromatic substances, markers, etc.,),

- the constituents of the pharmaceutical form administered to animals.

These particulars shall be supplemented by any relevant data concerning the container and,

where appropriate, its manner of closure, together with details of devices with which the

immunological veterinary medicinal product will be used or administered and which will

be delivered with the medicinal product. If the device is not delivered together with the

immunological veterinary medicinal product, relevant information about the device shall

be provided, where necessary for the assessment of the product.

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The usual terminology, to be used in describing the constituents of immunological

veterinary medicinal products:

- In respect of substances which appear in the pharmacopoeia, the main title of the

monograph in question, which will be obligatory for all such substances, with

reference to the pharmacopoeia concerned.

- In respect of other substances, the international non-proprietary name

recommended by the World Health Organization, which may be accompanied by

another non-proprietary name or, failing these, the exact scientific designation;

substances not having an international non-proprietary name or an exact scientific

designation shall be described by a statement of how and from what they were

prepared, supplemented, where appropriate, by any other relevant details.


In order to give the ‘quantitative particulars’ of the active substances of an immunological

veterinary medicinal product, it is necessary to specify whenever possible the number of

organisms, the specific protein content, the mass, the number of International Units (IU) or

units of biological activity, either per dosage-unit or volume, and with regard to the

adjuvant and to the constituents of the excipients, the mass or the volume of each of them.

with due allowance for the details provided in section 2b.

Where an International Unit of biological activity has been defined, this shall be used.

The units of biological activity for which no published data exist shall be expressed in such

a way as to provide unambiguous information on the activity of the ingredients, e.g. by

stating the immunological effect on which the method of determining the dose is based.

2a4 Product Development:

An explanation shall be provided with regard to the composition, and components,

supported by scientific data on product development. The overage, with justification

thereof, shall be stated.

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2b Description of the Manufacture Method

The name, address and responsibility of each manufacturer and each proposed production

site or facility involved in manufacturing and testing shall be indicated.

For this purpose, the description of the manufacture should include:

- the various stages of manufacture (including production of the antigen and

purification procedures) so that an assessment can be made of the reproducibility

of the manufacturing procedure and of the risks of adverse effects on the finished

products, such as microbiological contamination; the validation of key stages in the

production process shall be demonstrated and the validation of the production

process as a whole shall be demonstrated with provision of results of three

consecutive batches produced using the method described,

- in the case of continuous manufacture, full details concerning precautions taken to

ensure the homogeneity and consistency of each batch of the finished product,

- listing of all the substances at the appropriate steps where they are used, including

those which cannot be recovered in the course of manufacturing,

- the details of the blending, with the quantitative particulars of all the substances

used,

- a statement of the stages of manufacture at which sampling is carried out for control

tests during production.

2c Production and Control of the Starting Materials

For the purposes of this paragraph “starting materials” means all components used in the

production of the immunological veterinary medicinal product. Culture media consisting

of several components used for production of the active substance shall be regarded as one

starting material. Nevertheless, the qualitative and quantitative composition of the any

culture media shall be presented in so far as SFDA consider that this information is relevant

to the quality of the finished product and any risks that might be posed. If materials of

animal origin are used for preparation of these culture media, the animal species and the

tissue used have to be included.

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The dossier shall include the specifications, information on the tests to be conducted for

the quality control of all batches of starting materials and results for a batch for all

components used and shall be submitted.

2c1 Starting Materials listed in Pharmacopoeias

The monographs of the pharmacopoeia shall be applicable to all substances appearing in

starting materials.

The routine tests carried out on each batch of starting materials must be as stated in the

application for marketing authorization. If tests other than those mentioned in the

pharmacopoeia are used, proof must be supplied that the starting materials meet the quality

requirements of that pharmacopoeia.

In cases where a specification contained in a monograph of the pharmacopoeia might be

insufficient to ensure the quality of the substance, SFDA may request more appropriate

specifications from the applicant for marketing authorization.

When starting materials of animal origin are used, they shall comply with the relevant

monographs including general monographs and general chapters of the pharmacopoeia.

The tests and controls conducted shall be appropriate to the starting material.

The applicant shall supply documentation to demonstrate that the starting materials and the

manufacturing of the veterinary medical product is in comply with the requirements of the

Note for Guidance on minimising the risk of transmitting animal spongiform

encephalopathy agents via human and veterinary medicinal products, as well as with the

requirements of the corresponding monograph of the Pharmacopoeia.

Certificates of Suitability issued by the European Directorate for the Quality of Medicines

and Health Care, with reference to the relevant monograph of the Pharmacopoeia, may be

used to demonstrate compliance.

65

2c2 Starting Materials not listed in Pharmacopoeias

2c2.1 Starting Materials of Biological Origin

The description shall be given in the form of a monograph. Whenever possible, vaccine

production shall be based on a seed lot system and on established cell seeds. For the

production of immunological veterinary medicinal products consisting of serums, the

origin, general health and immunological status of the producing animals shall be indicated

and defined pools of source materials shall be used.

The origin, including geographical region, and history of starting materials shall be

described and documented.

For genetically engineered starting materials this information shall include details such as

the description of the starting cells or strains, the construction of the expression vector

(name, origin, function of the replicon, promoter enhancer and other regulator elements),

control of the sequence of DNA or RNA effectively inserted, oligonucleotidic sequences

of plasmid vector in cells, plasmid used for co-transfection, added or deleted genes,

biological properties of the final construct and the genes expressed, copy number and

genetic stability.

Seed materials, including cell seeds and raw serum for anti-serum production shall be

tested for identity and extraneous agents.

Information shall be provided on all substances of biological origin used at any stage in the

manufacturing procedure. The information shall include:

- details of the source of the materials,

- details of any processing, purification and inactivation applied, with data on the

validation of these process and controls during production,

- details of any tests for contamination carried out on each batch of the substance.

If the presence of extraneous agents is detected or suspected, the corresponding material

shall be discarded or used in very exceptional circumstances only when further processing

of the product ensures their elimination and/or inactivation; elimination and/or inactivation

of such extraneous agents shall be demonstrated.

When cell seeds are used, the cell characteristics shall be shown to have remained

unchanged up to the highest passage level used for the production.

66

For live attenuated vaccines, proof of the stability of the attenuation characteristics of the

seed has to be given.

Documentation shall be supplied to demonstrate that the seed materials, cell seeds, batches

of serum, Culture media and other material originating from animal species relevant for

the transmission of TSE comply with the Note for Guidance on minimizing the risk of

transmitting animal spongiform encephalopathy agents via human and veterinary

medicinal products, as well as with the corresponding monograph of the Pharmacopoeia.

Certificates of Suitability issued by the European Directorate for the Quality of Medicines

and Health Care, with reference to the relevant monograph of the European

Pharmacopoeia, can be used to demonstrate compliance.

2c2.2 Starting Materials of non-Biological Origin

The description shall be given in the form of a monograph under the following headings:

1. The name(s) of the starting material meeting the requirements of 2a2 shall be

supplemented by (any trade-name or scientific synonyms),

2. Description of starting material (set down in a form similar to that used in a

descriptive item in the Pharmacopoeia),

3. the function of the starting material,

4. methods of identification,

5. any special precautions which may be necessary during storage of the starting

material and, if necessary, its storage life shall be given.

2d Control Tests during the Manufacturing Process

The dossier shall include particulars relating to the control tests, which are carried out on

intermediate products with a view to verifying the consistency of the manufacturing

process and the final product. For inactivated or detoxified vaccines, inactivation or

detoxification shall be tested during each production run as soon as possible after the end

of the inactivation or detoxification process and after neutralization if this occurs, but

before the next step of production.

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2e Control Tests on the Finished Product

For all tests, the description of the techniques for analyzing the finished product shall be

set out in sufficiently precise detail for quality assessment.

The dossier shall include particulars relating to control tests on the finished product. Where

appropriate monographs exist, if test procedures and limits other than those mentioned in

the monographs of the Pharmacopoeia, proof must be supplied that the finished product

would, if tested in accordance with those monographs, meet the quality requirements of

that pharmacopoeia for the pharmaceutical form concerned. The application for marketing

authorization shall list those tests which are carried out on representative samples of each

batch of finished product. The frequency of the tests which are not carried out on each

batch shall be stated. Release limits shall be indicated.

Where available, chemical and biological reference material of the Pharmacopoeia shall be

used. If other reference preparations and standards are used, they shall be identified and

described in detail.

2e1 General Characteristics

The tests of general characteristics shall, wherever applicable, relate to the control of

average masses and maximum deviations, to mechanical, physical or chemical tests,

physical characteristics such as density, pH, viscosity, etc. For each of these characteristics,

specifications, with appropriate confidence limits, shall be established by the applicant in

each particular case.

2e2 Identification the Active Substance(s)

Where necessary, a specific test for identification shall also be carried out.

2e3 Batch Titre or Potency

A quantification of the active substance shall be carried out on each batch to show that each

batch will contain the appropriate potency or titre to ensure its safety and efficacy.

2e4 Identification and Assay of Adjuvants

Insofar as testing procedures are available, the quantity and nature of the adjuvant and its

components shall be verified on the finished product.

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Insofar as is necessary, the excipient(s) shall be subject at least to identification tests.

An upper and lower limit test shall be obligatory in respect of preserving agents; an upper

limit test for any other excipient components liable to give rise to an adverse reaction shall

be obligatory.

2e6 Safety Tests

Apart from the results of tests submitted in accordance with Part 3 particulars of safety

tests shall be submitted. These tests shall preferably be over dosage studies carried out in

at least one of the most sensitive target species and by at least the recommended route of

administration posing the greatest risk.

2e7 Sterility and Purity Test

Appropriate tests to demonstrate the absence of contamination by adventitious agents or

other substances shall be carried out according to the nature of the immunological

veterinary medicinal product, the method and the conditions of manufacture.

2e8 Residual Humidity

Each batch of lyophilised product shall be tested for residual humidity.

2e9 Inactivation

For inactivated vaccines, a test to verify inactivation shall be carried out on the product in

the final container unless it has been conducted at a late stage in-process.

2f Batch-to-Batch Consistency

In order to ensure that quality of the product is consistent from batch to batch and to

demonstrate conformity with specifications a full protocol of three consecutive batches

giving the results for all tests performed during production and on the finished product

shall be provided.

2g Stability

Description shall be given of the tests undertaken to support the shelf life proposed by the

applicant. These tests shall always be real-time studies; they shall be carried out on a

69

sufficient number of batches produced according to the described production process and

on products stored in the final container(s); these tests include biological and

physicochemical stability tests.

The conclusions shall contain the results of analyses, justifying the proposed shelf life

under all proposed storage conditions.

In the case of products administered in feed, information shall also be given as necessary

on the shelf life of the product, at the different stages of mixing, when mixed in accordance

with the recommended instructions.

Where a finished product requires reconstitution prior to administration or is administered

in drinking water, details of the proposed shelf life are required for the product

reconstituted as recommended. Data in support of the proposed shelf life for the

reconstituted product shall be submitted.

Stability data obtained from combined products may be used as preliminary data for

derivative products containing one or more of the same components.

The proposed in-use shelf life shall be justified. The efficacy of any preservative system

shall be demonstrated.

Information on the efficacy of preservatives in other similar immunological veterinary

medicinal products from the same manufacturer may be sufficient.

Refer to the VICH stability testing guidelines:

http://www.vichsec.org/guidelines/biologicals/bio-quality/stability.html

Moreover, a certain SFDA stability testing guidelines been established and are under

review by the SFDA standard setting departments and will be published as soon as possible.

2h Other Information

Information relating to the quality of the immunological veterinary medicinal product not

covered by the previous sections may be included in the dossier.

http://www.vichsec.org/guidelines/biologicals/bio-quality/stability.html

70

Part 3 Safety Documentation

3a General Requirements

The safety tests shall show the potential risks from the immunological veterinary medicinal

product, which may occur under the proposed conditions of use in animals: these shall be

evaluated in relation to the potential benefits of the product.

Where immunological veterinary medicinal products consist of live organisms, especially

those, which could be shed by vaccinated animals, the potential risk to unvaccinated

animals of the same or of any other potentially exposed species shall be evaluated.

The safety studies shall be carried out in the target species. The dose to be used shall be

the quantity of the product to be recommended for use and the batch used for safety testing

shall be taken from a batch or batches produced according to the manufacturing process

described in Part 2 of the application.

In the case of an immunological veterinary medicinal product containing a live organism,

the dose to be used in the laboratory tests described in sections 3b1 and 3b2 shall be the

quantity of the product containing the maximum titre. If necessary the concentration of the

antigen may be adjusted to achieve the required dose. For inactivated vaccines the dose to

be used shall be that quantity recommended for use containing the maximum antigen

content unless justified.

The safety documentation shall be used for assessment of the potential risks which may

result from the exposure of human beings to the veterinary medicinal product, for example

during its administration to the animal.

3b Laboratory Tests

3b1 Safety of One Dose

The immunological veterinary medicinal product shall be administered at the

recommended dose and by each recommended route of administration to animals of each

species and category in which it is intended for use, including animals of the minimum age

of administration. The animals shall be observed and examined for signs of systemic and

local reactions. Where appropriate, these studies shall include detailed post-mortem

macroscopic and microscopic examinations of the injection site. Other objective criteria

shall be recorded, such as rectal temperature and performance measurements.

The animals shall be observed and examined until reactions may no longer be expected,

71

but in all cases, the observation and examination period shall be at least 14 days after

administration.

This study may be part of the repeated dose study required under section 3b3 or omitted if

the results of the overdose study required section 3b2 have revealed no signs of systemic

or local reactions.

3b2 Safety of an Overdose

Only live immunological veterinary medicinal products require overdose testing. An

overdose of the immunological veterinary medicinal product shall be administered by each

recommended route(s) of administration to animals of the most sensitive categories of the

target species, unless the selection of the most sensitive of several similar routes is justified.

In the case of immunological veterinary medicinal products administered by injection, the

doses and route(s) of administration shall be chosen to take account of the maximum

volume, which can be administered at any one single injection site. The animals shall be

observed and examined for at least 14 days after administration for signs of systemic and

local reactions. Other criteria shall be recorded, such as rectal temperature and performance

measurements.

Where appropriate, these studies shall include detailed post-mortem macroscopic and

microscopic examinations of the injection site if this has not been done under section 3b1.

3b3 Safety of the Repeated Administration of One Dose

In the case of immunological veterinary medicinal products to be administered more than

once, as part of the basic vaccination scheme, a study of the repeated administration of one

dose shall be required to reveal any adverse effects induced by such administration. These

tests shall be carried out on the most sensitive categories of the target species (such as

certain breeds, age groups), using each recommended route of administration.

The animals shall be observed and examined for at least 14 days after the last

administration for signs of systemic and local reactions. Other objective criteria shall be

recorded, such as rectal temperature and performance measurements.

3b4 Examination of Reproductive Performance

Examination of reproductive performance shall be considered when data suggest that the

72

starting material from which the product is derived may be a potential risk factor.

Reproductive performance of males and non-pregnant and pregnant females shall be

investigated with the recommended dose and by the most sensitive route of administration.

In addition, harmful effects on the progeny, as well as teratogenic and abortifacient effects,

shall be investigated.

These studies may form part of the safety studies described in sections 3b1, 3b2 and 3b3

or of the field studies provided for in section 3c.

3b5 Examination of Immunological Functions

Where the immunological veterinary medicinal product might adversely affect the immune

response of the vaccinated animal or of its progeny, suitable tests on the immunological

functions shall be carried out.

3b6 Special Requirements for Live Vaccines

3b6.1 Spread of the Vaccine Strain

Spread of the vaccine strain from vaccinated to unvaccinated target animals shall be

investigated, using the recommended route of administration most likely to result in the

spread. Moreover, it may be necessary to investigate the spread to non-target animal

species which could be highly susceptible to a live vaccine strain.

3b6.2 Dissemination in the Vaccinated Animal

Faeces, urine, milk, eggs, oral, nasal and other secretions shall be tested for the presence

of the organism as appropriate. Moreover, studies may be required of the dissemination of

the vaccine strain in the body, with particular attention being paid to the predilection sites

for replication of the organism. In the case of live vaccines for zoonoses to be used for food

producing animals, these studies must shall take particularly into account the persistence

of the organism at the injection site.

3b6.3 Reversion to Virulence of Attenuated Vaccines

Reversion to virulence shall be investigated with the master seed. If the master seed is not

available in sufficient quantity the lowest passage seed used for the production shall be

examined. Use of another passage option shall be justified. The initial vaccination shall be

carried out using the route of administration most likely to lead to reversion to virulence.

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Serial passages shall be made in target animals through five groups of animals, unless there

is justification to make more passages or the organism disappears from the test animals

sooner. Where the organism fails to replicate adequately, as many passages as possible

shall be carried out in the target species.

3b6.4 Biological Properties of the Vaccine Strain

Other tests may be necessary to determine as precisely as possible the intrinsic biological

properties of the vaccine strain (e.g. neurotropism).

3b6.5 Recombination or Genomic Reassortment of Strains

The probability of recombination or genomic reassortment with field or other strains shall

be discussed.

3b7 User Safety (URA)

This section shall include a discussion of the effects found in the preceding sections, which

shall relate those effects to the type and extent of human exposure to the product with a

view to formulating appropriate user warnings and other risk management measures.

3b8 Study of Residues

For immunological veterinary medicinal products, it will normally not be necessary to

undertake a study of residues.

However, where adjuvants and/or preservatives are used in the manufacture of

immunological veterinary medicinal products, consideration shall be given to the

possibility of any residue remaining in the foodstuffs. If necessary, the effects of such

residues shall be investigated.

A proposal for a withdrawal period shall be made and its adequacy shall be discussed in

relation to any residue studies which have been undertaken.

3b9 Interactions

If there is a compatibility statement with other veterinary immunological products in the

summary of product characteristics the safety of the association shall be investigated. Any

other known interactions with veterinary medicinal products shall be described.

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3c Field Studies

Unless justified, results from laboratory studies shall be supplemented with data from field

studies, using batches according to the manufacturing process described in the marketing

authorization application. Both safety and efficacy may be investigated in the same field

studies.

3d ERA (Environmental Risk Assessment)

The purpose of the environmental risk assessment is to assess the potential harmful effects,

which the use of the product may cause to the environment and to identify any

precautionary measures, which may be necessary to reduce such risks.

This assessment shall normally be conducted in two phases. The first phase of the

assessment shall always be performed.

It shall indicate the potential exposure of the environment to the product and the level of

risk associated with any such exposure, taking into account in particular the following

items:

- the target animal species and the proposed pattern of use,

- the method of administration, in particular the likely extent to which the product

will enter directly into the environmental system,

- the possible excretion of the product, its active substances into the environment by

treated animals, persistence in such excreta,

- the disposal of unused or waste product.

In the case of live vaccine strains which may be zoonotic, the risk to humans shall be

assessed.

Where the conclusions of the first phase indicate potential exposure of the environment to

the product, the applicant shall proceed to the second phase and evaluate the potential

risk(s) that the veterinary medicinal product might pose to the environment. Where

necessary, further investigations on the impact of the product (soil, water, air, aquatic

systems, non-target organisms) shall be carried out.

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3e Assessment of Products Containing or Consisting of GMO (Genetically Modified

Organisms)

In this section the applicant should describes the format in which the particulars relevant

to the environmental risk assessment.

In the case of veterinary medicinal products containing or consisting of genetically

modified organisms the application shall also be accompanied by the documents required

by international guidance and describes the format in which the particulars relevant to the

environmental risk assessment.

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Part 4 Efficacy documentation

4a General Principles

The purpose of the trials described in this Part is to demonstrate or to confirm the efficacy

of the immunological veterinary medicinal product. All claims made by the applicant with

regard to the properties, effects and use of the product, shall be fully supported by results

of specific trials contained in the application for marketing authorization.

4b Performance of Trials

All efficacy trials shall be conducted in accordance with a fully considered detailed

protocol, which shall be recorded in writing prior to commencement of the trial. The

welfare of the trial animals shall be subject to veterinary supervision and shall be taken

fully into consideration during the elaboration of any trial protocol and throughout the

conduct of the trial.

Field trials shall be conducted in accordance with established principles of good clinical

practice, unless otherwise justified.

Before the commencement of any field trial, the informed consent of the owner of the

animals to be used in the trial shall be obtained and documented. In particular, the animal

owner shall be informed in writing of the consequences of participation in the trial for the

subsequent disposal of treated animals or for the taking of foodstuffs from treated animals.

A copy of this notification, countersigned and dated by the animal owner, shall be included

in the trial documentation

4c General Requirements

The choice of antigens or vaccine strains shall be justified on the basis of epizoological

data.

Efficacy trials carried out in the laboratory shall be controlled trials, including untreated

control animals unless this is not justified for animal welfare reasons and efficacy can be

otherwise demonstrated.

In general, these laboratory trials shall be supported by trials carried out in field conditions,

including untreated control animals.

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All trials shall be described in sufficiently precise details so as to be reproducible in

controlled trials, carried out at the request of the SFDA. The investigator shall demonstrate

the validity of all the techniques involved. All results obtained, whether favorable or

unfavorable, shall be reported.

The efficacy of an immunological veterinary medicinal product shall be demonstrated for

each category of target animal species recommended for vaccination, by each

recommended route of administration and using the proposed schedule of administration.

The influence of passively acquired and maternally derived antibodies on the efficacy of a

vaccine shall be adequately evaluated, if appropriate. Unless justified, the onset and

duration of immunity shall be established and supported by data from trials.

The efficacy of each of the components of multivalent and combined immunological

veterinary medicinal products shall be demonstrated. If the product is recommended for

administration in combination with or at the same time as another veterinary medicinal

product, they shall be shown to be compatible.

Whenever a product forms part of a vaccination scheme recommended by the applicant,

the priming or booster effect or the contribution of the veterinary immunological product

to the efficacy of the scheme as a whole shall be demonstrated.

The dose to be used shall be the quantity of the product to be recommended for use and the

batch used for efficacy testing shall be taken from a batch or batches produced according

to the manufacturing process described in part 2 of the application.

If there is a compatibility statement with other immunological products in the summary of

product characteristics, the efficacy of the association shall be investigated. Any other

known interactions with any other veterinary medicinal products shall be described.

Concurrent or simultaneous use may be allowed if supported by appropriate studies.

For diagnostic immunological veterinary medicinal products administered to animals, the

applicant shall indicate how reactions to the product are to be interpreted.

For vaccines intended to allow a distinction between vaccinated and infected animals

(marker vaccines), where the efficacy claim is reliant on in vitro diagnostic tests, sufficient

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data on the diagnostic tests shall be provided to allow adequate assessment of the claims

related to the marker properties.

4d Laboratory Trials

In principle, demonstration of efficacy shall be undertaken under well-controlled

laboratory conditions by challenge after administration of the immunological veterinary

medicinal product to the target animal under the recommended conditions of use. Insofar

as possible, the conditions under which the challenge is carried out shall mimic the natural

conditions for infection. Details of the challenge strain and its relevance shall be provided.

For live vaccines, batches containing the minimum titre or potency shall be used unless

justified. For other products, batches containing the minimum active content shall be used

unless otherwise justified.

If possible, the immune mechanism (cell-mediated/humoral, local/general classes of

immunoglobulin) which is initiated after the administration of the immunological

veterinary medicinal product to target animals by the recommended route of administration

shall be specified and documented.

4e Field Trials

Unless justified, results from laboratory trials shall be supplemented with data from field

trials, using batches representative of the manufacturing process described in the marketing

authorization application. Both safety and efficacy may be investigated in the same field

study.

Where laboratory trials cannot be supportive of efficacy, the performance of field trials

alone may be acceptable.

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V. References

Framework for a correlation table (NTA: CTD) for ASMFs/Part 2 in CTD format for

dossiers for veterinary medicinal products.

Guideline on the scientific data requirements for a Vaccine Antigen Master File

(vamf).

Notice to applicants of veterinary medicinal products (Presentation and content of the

dossier), Directorate – General for Health and Food safety, European Commission,

2015.

Guideline on quality data requirements for veterinary medicinal products intended for

minor use or minor species (MUMS)/limited market.

Concept paper for the development of a guideline on data 4 requirements for vaccine

antigen master files (VAMF).

Advice implementing measures under Article 146(2) of Regulation (EU) 2019/6 on

veterinary medicinal 176 products – Scientific recommendation on the revision of

Annex II to Regulation (EU) 2019/6 on 177 veterinary medicinal products

(EMA/CVMP/351417/2019).

Regulations (law) of veterinary products in Gulf Cooperation Council (GCC).

VICH stability guidelines.

Studies to evaluate the safety of residues of veterinary Drugs in human food:

Reproduction testing.

Studies to evaluate the safety of residues of veterinary drugs in human food:

developmental toxicity testing.

Studies to evaluate the safety of residues of veterinary drugs in human food: general

approach to testing.